2.1 Mastalgia
In the typical life-cyle of modern women, the mid-thirties until the cessation of menstrual periods is defined as “peri-menopause”. Women are classified as perimenopausal if menses have been experienced in the last 12 months, but with irregularity or changes in menstrual flow. During this stage of life women suffer increasing incidence of both recurrent breast pain, or “mastalgia”, and endometriosis, describing the painful condition of persistence of abnormal endometrial tissue in the abdominal cavity. These two conditions, common to the perimenopause, are poorly understood and presently lack medical therapy that is both effective and reasonably free of side effects (Prior, J. C., “Perimenopause: the complex endocrinology of the menopausal transition”, Endocr. Rev., 19, pages 397-428, 1998).
While a contributing role of estrogen status has been suspected in these conditions, few consistent abnormalities in endocrine status have been identified. Circulating estrogen levels are normal in both mastalgia and endometriosis patients. There is accumulating evidence that describes diminished progesterone production during the perimenopause that may create a relative “dominance” in the activity of estrogen. However, no one theory or endocrine imbalance explains the occurrence of mastalgia and endometriosis. (Santoro, N., Rosenberg, J., et al.,“Characteristics of reproductive hormonal dynamics in the perimenopause”, J. Clinical Endocrinology and Metab., 81, pages 1495-501, 1996).
Recurrent, cyclical breast pain or “mastalgia” is one of the most common reasons for women's visits to their doctors. It has been estimated that 50-70% of all women experience significant mastalgia at some point in their life. In its most common form, mastalgia is a chronic condition of recurring pain, which is worse during the few days before menses (Blue, J., Harman, J., et al., “Mastalgia review: St. Marks Breast Centre”, New Zealand Medical Journal, 111(1059), pages 33-34, 1998). Traditionally, treatment choices for mastalgia have ranged from dietary manipulation (caffeine, fat, and alcohol reduction) or evening primrose oil to hormonal medications (bromocriptine and danazol) for severe breast pain. Bromocriptine (Parlodel) and danazol have a response rate of 70%, but have reported adverse side effects of up to 30-35% (Gateley, C. A. and Mansen, R. E., “Management of the painful and nodular breast”, British Medical Bulletin, 47, 284-94, 1991; Nazli K., et al. Controlled trial of the prolactin inhibitor bromocriptine (Parlodel) in the treatment of severe cyclical mastalgia. British Journal of Clinical Practice. 1989; 43(9): 322-7; Kontosolis K. et al., Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecol. Endolcrinol. 1997; 11, page 393-397). The use of medroxyprogesterone acetate to support levels of progesterone, possibly low in this condition, proved relief no better than placebo in a controlled trial. (Maddox, P. R., Harrison, B. J., et al., “A randomized controlled trial of medroxyprogesterone acetate in mastalgia”, Annals of the Royal College of surgeons of England, 72(2), pages 71-6, 1990).
The approach of dietary supplementation for mastalgia has been explored by earlier investigators. This included the addition of high doses of evening primrose oil, beta carotene, and vitamin A to the diet of affected women. Evening primrose oil is used by British physicians as an initial intervention to control mastalgia because of its non-hormonal composition. Though it has been found to normalize the ratio of essential fatty acids to saturated fatty acids in the serum of women with mastalgia, the therapy requires 3 to 4 months for benefit. Improvements were seen in up to 40% of patients but side effects included bloating and nausea (Maddox, P. R., “The management of mastalgia in the UK”, Hormone Research, 32, pages 21-27, 1989). Italian researchers explored the addition of combinations of beta carotene and Vitamin A (retinol) in the management of mastalgia. (Santamaria L, Dell'Orti, M., et al., “Beta-carotene supplementation associated with intermittent retinol administration in the treatment of pre-menopausal mastodynia,”, Boll Chim Far, 128, pages 284-287, 1989). Some success was reported, but the high doses of retinol required (150-300,000 I.U per day) are in the range associated with significant side effects which include headache, skin lip and mouth dryness, nausea, dizziness, and alopecia. Based on the common occurrence of mastalgia as a disorder in women, the need exists for more effective therapy with acceptable risks and side effects (Ashley B., “Mastalgia”, Lippincotts Primary Care Practice. 1998; 2(2): 189-93).
2.2 Endometriosis
Endometriosis is a disease that affects as many as 15% of fertile women and up to 50% of infertile women. Its occurrence increases with age and is greatest in the perimenopausal years (Tzingounis V A, and Cardamakis E., “Modern approach to endometriosis”, Annals of the New York Academy of Sciences, 816, pages 320-330, 1997). Endometriosis refers to the presence of functional endometrial glands and stroma in abnormal locations outside the uterine cavity. Despite extensive research, the natural history and pathogenisis of endometriosis is still poorly understood and remains controversial. As with mastalgia, most therapeutic approaches have been directed at hormonal therapy. The most common therapy involves the use of danazol. Danazol is a synthetic steroid with androgenic action suppressing the pituitary gland cycling necessary for menstrual periods. Amenorrhea, or lack of menstrual periods results. Though providing some relief from the pain of endometriosis adverse side effects are experienced in up to 80% of women using Danazol (Greenblatt R B, Dmowski, W. P., et al. “Clinical studies with an anti-gonadotropin—danazol”, Fertil Steril, 22, page 102, 1971). Notably these side effects include weight gain, fluid retention, acne, decreased breast size, hot flushes and mood changes. In addition to danazol, other hormonal manipulations used in the management of endometriosis involve use of gonadotropin releasing hormone analogues (GnRH) and the drug gestrinone, a synthetic steroid derived from 19-nortestosterone. The side effects, associated with these therapies are significant and include the spectrum of symptoms associated with hypoestrogenism and menopause. These include hot flushes, night sweats, and osteoporosis. (Telimaa, E. J., Puolakka, J., et al., “Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis”, Gynecol Endocrinol, 1, page 51, 1987, and Thomas E. J., Cooke, I. D., et al., “Impact of gestrinone on the course of asymptomatic endometriosis”, Br. Med J., 294, page 272, 1987). Clearly, more benign approaches to the management of the pain of endometriosis are needed.
2.3 Dietary Indoles
Diindolylmethane (DIM), as well as its precursor, Indole-3-carbinol (I3C), and cogener, 2-(Indol-3-ylmethyl)-3,3′-diindolylmethane (LTR-1) are natural phytochemicals and part of the family of dietary indoles discovered in cruciferous vegetables. DIM and I3C are found in cruciferous vegetables including broccoli, cauliflower, cabbage and Brussels sprouts (Bradfield C A and Bjeldanes L F, High performance liquid chromatographic analysis of anticarcinogenic indoles in Brassica oleracea. J Agric. Food Chem. 1987; 35:46-49). DIM, together with the linear trimer, LTR-1, are formed from the precursor indole, I3C, after the enzymatic release of I3C from parent glucosinolates found in all cruciferous vegetables.
It is now known that there is a connection between dietary cruciferous indoles and estrogen metabolism. H. Leon Bradlow, Ph.D. and his group at the Strang Cancer Prevention Laboratory in New York were the first to establish the link between phytonutrients from cruciferous vegetables and estrogen metabolism. They showed that supplemental use of a I3C can act to promote a dramatic change in the metabolism of estrogen Michnovicz J J, et al., Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997 May 21; 89(10):718-23. This change in metabolism has the power to greatly reduce estrogen exposure as a risk for cancer and provides a dietary approach to improving estrogen metabolism. When cruciferous phytochemicals are added to the diet its metabolism is shifted. This produces a predominance of 2-hydroxy and 2-methoxyestrogens (Michnovicz J J, et. al., Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997 May 21; 89(10):718-23). An increased proportion of 2-hydroxy metabolites is correlated to protection from breast cancer. This relationship has been documented in case-control studies (Ho G H, et al. Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann Acad Med Singapore 1998; 27:294-299, and Schneider J., et al., Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci USA 1982; 79: 3047-3051). The 2-hydroxy metabolites have been called “good estrogens (Bradlow H L, et al., 2-hydroxyestrone: the ‘good’ estrogen. J Endocrinol. 1996 September; 150 Suppl:S259-65), and may function as antioxidants (Komura S, et al., Catecholestrogen as a natural antioxidant. Ann N Y Acad Sci. 1996 Jun 15; 786:419-429).
With regard to prior art and the dietary indoles, the supplemental use of I3C, which converts to DIM and LTR-1 after passage through the stomach, has been the subject of a U.S. Pat. No. 5,895,787) describing the use of I3C and related dietary indoles to reduce the symptoms of fibromyalgia. Despite this use, no relationship between fibromyalgia and estrogen status has been documented (Bengtsson A., Henriksson, K. G., “Primary fibromyalgia. A clinical and laboratory study of 55 patients.”, Scand J. Rheumatol, 15(3) pages 340-7, 1986) Published reports have demonstrated the usefulness of dietary supplementation with I3C in recurrent laryngeal papillomatosis and cervical dysplasia. (Rosen, C. A., Woodson, G. E. et al., “Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis, Otolaryngology Head Neck Surgery, 118, pages 810-5, 1998, and Jin L., Qi, M., et al., “Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice”, Cancer Research, 59(16), pages 3991-7, 1999) These are both diseases related to the action of the human papilloma virus and may represent conditions sensitive to estrogen metabolic status. Use of DIM and LTR-1 in absorption enhancing formulations for improving the balance of estrogen metabolites has been the subject of earlier investigation by the present inventor and provides the basis of U.S. patent application Ser. No. 09/053,180. This prior work has allowed for the present investigation of the use dietary indoles as dietary supplements to beneficially impact mastalgia and endometriosis.
While previous work with dietary indoles, like DIM, has indicated their ability to impede the growth of breast cancer in animals (Chen, I., McDougal, A., et al., “Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane,” Carcinogenesis, 19(9), 1631-9, 1998) no reports exist as to the usefulness of cruciferous phytochemicals in managing mastalgia or endometriosis.